Expert Q&A: Developments in Noninvasive Prenatal Testing

Diana W. Bianchi is the director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a senior investigator in the Center for Precision Health Research at the National Human Genome Research Institute. She received her MD from Stanford and her postgraduate training in pediatrics, medical genetics, and neonatal-perinatal medicine at Harvard. Bianchi’s research focuses on noninvasive prenatal screening and the development of novel fetal therapies for genetic disorders. She has published over 350 peer-reviewed articles and is a member of the National Academy of Medicine. She received an honorary PhD from the University of Amsterdam in 2020. Bianchi discusses key developments in noninvasive prenatal testing, as well as her recent research.

Q: How has prenatal genetic testing evolved over the years, and what are some of the major advancements that have had a significant impact on the field?

A: Prenatal screening has largely focused on detecting the most common fetal chromosome abnormalities that are associated with live births and intellectual disability, specifically trisomies 21, 13, and 18. Prenatal genetic screening generally consists of either sonographic imaging (that examines fetal growth patterns, whether a single or multiple fetuses are present, whether a fetus is moving and swallowing normally, whether structural abnormalities are present), and/or measurement of biochemical analytes that are indirect measures of fetal or placental function. Starting in 2011, massively parallel sequencing (commonly called next-generation sequencing) of cell-free DNA fragments that circulate in the plasma of a pregnant woman was shown to be a more sensitive and accurate way of screening for fetal chromosome imbalance.

Q: How is noninvasive prenatal genetic testing (NIPT) performed? What are the specific conditions or abnormalities they can detect?

A: There are three main methods: whole genome or targeted DNA sequencing, measurement of single nucleotide polymorphisms, and hybridization to chromosome microarrays. These methods sequence naturally fragmented DNA that originates in the placenta and serves as a proxy for the fetus. All of these techniques detect areas of the genome that are present in excess or are deleted when compared to a normal reference genome. In some versions of NIPT, the sex chromosomes are analyzed, which can reveal fetal sex, as well as anomalies in the number of sex chromosomes in conditions such as Turner syndrome (45, X) and Klinefelter syndrome (47, XXY).

Q: What factors are to be considered when choosing tests to guide diagnostic decisions?

A: Noninvasive prenatal testing (NIPT) is a screening test designed to identify a population of pregnant women who are at high risk for having a fetus with a chromosome abnormality. The results are not diagnostic. There are reasons other than a fetal abnormality that can cause an abnormal NIPT result. If the NIPT result is abnormal, global clinical guidelines recommend confirmation with a diagnostic test such as an amniocentesis or chorionic villus sampling.

Q: How is the accuracy and reliability of clinically available NIPT kits determined? What organizations are responsible for regulatory oversight of commercially available NIPT kits?

A: NIPT is performed in the US as a laboratory-developed test (LDT). NIPT is not FDA-approved at the present time. Most NIPTs are done in large commercial laboratories which each do their own quality assurance.

Q: What are the main challenges or limitations associated with NIPT? How are they being addressed in current clinical practice?

A: Some of the main challenges include the fact that, in the US, there are many laboratories providing testing, and they each utilize different techniques and bioinformatics algorithms to analyze the results. There are no standards for how to report test results, so a variable amount of information is reported. Care providers need more education regarding the significance of nonreportable or unusual test results.

Q: Are there disparities in access or accuracy of NIPT or interpretation of its results for racial or ethnic minorities? What efforts are being made to address these issues?

A: Unlike single gene analysis, in which it is important to understand racial and ethnic variation at the DNA sequence level, NIPT works by sequencing long segments of DNA and counting ratios between a reference sample and a patient-specific sample. This is not significantly affected by race or ethnicity. The more important issue is ensuring that all pregnant people have access to this testing if they wish to have it. About half of the pregnancies in the US are covered by state Medicaid programs, and each of these programs differs in their policies regarding coverage of NIPT. Some states will cover the test for women at high risk of having an aneuploid fetus, others will cover all pregnant women regardless of risk, and still others do not cover NIPT at all. The state of California has a program that provides first-line NIPT to all pregnant people.

Q: Can you tell us about your research on NIPT? What are some of the recent highlights of your work, and what are you most excited about for the future?

A: We are currently very interested in whether NIPT can also act as a liquid biopsy to detect cancer in the mother. If there is a tumor present, it can shed fragments of DNA into the mother’s plasma like the placenta does. This may result in very unusual NIPT results. We are performing a study at the Clinical Center at the NIH in which we are doing a full medical work-up, along with blood tests and imaging in pregnant women to determine why their NIPT results are abnormal. All the pregnant women enrolled in the study have a fetus with normal sonographic or diagnostic chromosome results. We are finding that approximately 50 percent of the pregnant women in our study have cancer. This is surprising because they generally perceive themselves to be well and are asymptomatic.

Q: If the cancer is detected when the women are asymptomatic, what does it mean for treatment and prognosis? Is NIPT more likely to detect cancer at an earlier stage or have a preponderance for detecting a certain type of cancer?

A: This is an ongoing study, so it is premature to conclude at what stage the cancers can be detected or whether certain cancer types are more likely to be found. However, all participants who enroll in the study are given their results in real time. The results are actionable, which means that we make a follow-up plan with the participant for their clinical management after all of the research tests results are available.

Q: How do you envision the outcomes of your study may impact the counseling and care of pregnant women with such incidental findings?

A: Our goal is to generate the evidence needed by care providers to determine the next steps when an unusual NIPT result is found that is not present in the fetus. Currently, there is confusion and wide variation in the subsequent approaches. Further, in most cases, insurance will not cover comprehensive maternal imaging studies without evidence of its effectiveness. Lastly, our study may demonstrate that the standard NIPT platform can also work as a liquid biopsy to screen for cancer in non-pregnant people.

Q: What do you expect the NIPT landscape will look like going forward, especially in the age of artificial intelligence and big data? How can clinical laboratories best prepare for this future?

A: Going forward, the NIPT landscape will shift from detection of fetal chromosome abnormalities to prediction of complications of pregnancy, such as infection, risk for preterm delivery, and risk for preeclampsia. This will allow pregnant women to receive personalized obstetric care that addresses their specific risks. Artificial intelligence and machine learning will be helpful in analyzing and recognizing certain DNA sequencing patterns that are associated with specific conditions. There is also a tremendous need for genetic counselors to communicate the significance of different sequencing results. AI-generated avatars are already in a pilot phase. They are being designed as assistants to perform genetic counseling.